Dual injections
of cabotegravir, an experimental integrase inhibitor, and the non-nucleoside
reverse transcriptase inhibitor (NNRTI) rilpivirine, currently available as a pill (Edurant), maintained viral suppression
among treatment-experienced people switching from a standard oral regimen and
among previously untreated people after a short three-drug induction period.

What's more, study
participants expressed a high level of satisfaction with monthly injections
compared with daily pills, and nearly all said they would prefer to use the
injectable method, reported Dr Susan Swindells of the University of Nebraska Medical Center and Dr Chloe
Orkin of Queen Mary
University of London.

The phase II LATTE trials previously
demonstrated that a simplified oral regimen of cabotegravir plus
rilpivirine is
effective as maintenance therapy. This
supported the evaluation of injectable formulations of the two drugs in
previously untreated patients. As
reported at the 2016 International AIDS Conference, 91% of people who
received the injections every 4 weeks and 92% of those who did so every 8 weeks
had undetectable viral load at week 48.

This set the stage for
larger phase III trials. ATLAS (Antiretroviral Therapy as Long-Acting Suppression) evaluated injectable cabotegravir plus rilpivirine in people who
switched from a standard oral antiretroviral combination with an undetectable
viral load, while FLAIR (First Long-Acting Injectable Regimen) tested
the injectables in people starting HIV treatment for the first time.

Cabotegravir and
rilpivirine were administered as two separate intramuscular jabs, with the
buttocks being the preferred injection site. All injections were given by
health care providers. Patients were asked to return to their clinics each
month and were given a seven-day window in which to do so. Adherence was good
in both studies, with almost all participants receiving monthly treatment
within this window.

Use of injectable therapy would be "a big paradigm shift" in
how we offer treatment, according to Orkin. "It can be done – we haven’t
done it in HIV, but it's done in other areas of medicine," she said, pointing
out that long-acting depot formulations are widely used for psychiatric drugs and
contraception is commonly administered as injections every month or two.

Switching to injectables

The ATLAS trial, presented by Swindells, included 616
treatment-experienced patients. A third were women, two thirds were white,
about a quarter were black and the median age was 42 years. They had been on antiretroviral therapy for a
median of four years, all had viral suppression and the median CD4 count was
653 cells/mm3.

At baseline, half were taking NNRTI-based regimens, a
third were taking integrase inhibitors and 17% were on protease inhibitors.
They were randomly assigned to either stay on their current oral regimen or
switch to injectable cabotegravir
and rilpivirine. To ensure safety, participants in the latter group took
cabotegravir and rilpivirine pills for a month before switching to injections.

Rates of virological
non-response, defined as HIV RNA at or above 50 copies/ml, were very low in
both groups: 1.6% with injectable cabotegravir and rilpivirine versus 1.0% with
the continued oral regimen. Virological success rates were 92.5% and 95.5%,
respectively. These results showed that the injectables were non-inferior to
continued oral therapy.

Three individuals who received the injectables (two from Russia and one from
France) had confirmed virological failure at week 8, 12 and 20 and showed
evidence of reverse transcriptase or integrase resistance-association
mutations. All had 'A' subtypes of HIV.

Starting with injectables

The FLAIR trial, presented by Orkin, included 556
people starting their first HIV treatment. Just over 20% were women, nearly
three quarters were white, 18% were black and the median age was 34 years. At
baseline, a fifth had a viral load of 100,000 copies/ml or higher and the
median CD4 count was 444 cells/mm3.

Participants started with a three-drug induction
regimen of co-formulated dolutegravir/abacavir/lamivudine (Triumeq) for 20 weeks to bring down virus levels. They were then
randomised to either stay on this regimen or switch to injectable cabotegravir and rilpivirine, again
starting with oral formulations of these drugs for the first month.

Here too, virological
non-response rates were low, at 2.1% in the injectable group and 2.5% in the
oral therapy group. Virological success rates were 93.6% and 93.3%, respectively,
again demonstrating non-inferiority. Three people, all from Russia and with HIV
'A' subtypes, had confirmed virological failure and showed evidence of
resistance-associated mutations.

Safety and satisfaction

In both studies,
pharmacokinetic data showed that cabotegravir and rilpivirine concentrations in
the blood remained above effective thresholds throughout the study and were
similar to levels reached with the corresponding oral formulations.

Treatment was generally safe and well tolerated. Serious
adverse events were rare among people using cabotegravir and rilpivirine (none in ATLAS and one in
FLAIR). There were no cases of drug hypersensitivity or liver toxicity.
In both trials, 3% of participants stopped
treatment with the injectables due to adverse events.

Injection site reactions
– predominately pain – occurred in 20% to 30% of participants. These were
most common early in the study, were generally mild or moderate and improved
over time, lasting a median of three days. Four people in ATLAS and three in
FLAIR dropped out due to injection site reactions.

The researchers also
evaluated patient satisfaction and preferences, finding that those receiving the
injectables were more satisfied with their treatment. The increase in
satisfaction was especially notable in ATLAS, where participants were coming off
daily oral therapy. A large majority said they preferred the injectables over
pills (86% of all patients and 97% of survey respondents in ATLAS; 91% and 99%,
respectively, in FLAIR).

Swindells acknowledged that as a provider, she found it surprising that
some patients prefer injections to pills, but they do. "They like not
having to worry about taking their pills every day…they get their injection and
they're good to go," she said. "They don't have to think about having
HIV every day, they don't have to worry about co-workers or housemates seeing
their pill bottles – there's maybe some relief of the stigma of HIV if they
don't have to think about it every day."

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends
checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.